The toxic heavy metal cadmium is a high priority contaminant identified at more than one third of all Superfund Sites. While cadmium is a known and well-studied carcinogen, here we will address cadmium's effects as a developmental toxicant. Newborns exposed to cadmium during the prenatal period have increased risk for poor birth outcomes, including low birthweight. In addition to the immediate postnatal concerns, low birthweight is also associated with increased risk for chronic diseases later in life, such as diabetes, hypertension, and cardiovascular disease. While poor birth outcomes have been associated with environmental exposure to cadmium and other metals, the underlying biological mechanisms remain under studied. Integrating our preliminary findings and our interest in understanding how metal exposure influences pregnancy outcome in the United States, we will examine gene-environment interactions that influence cadmium-induced signaling of inflammatory response genes and will determine the association of pathway modulation with birthweight. We hypothesize that gene-environment interactions influence cadmium's effects on signaling of inflammatory response genes and that this signaling is associated with newborn birth outcomes. This study will use complementary in vitro and in vivo approaches to test our hypothesis. To identify genes that influence cadmium-induced toxicity, we will use a panel of cell lines derived from a genetically diverse human population. The integrated in vivo aims will assess the impact of fetal genotypes of inflammatory response genes on newborn birthweight and the interaction effects between fetal genotypes and cadmium exposure. The modulation of the expression levels of members of inflammatory response genes in newborns and association with maternal cadmium exposure will be determined. The role of DNA methylation in controlling the gene expression alterations will be established. The results obtained from the proposed research will help to elucidate molecular pathways associated with cadmium-induced toxicity and disease.